Project Summary/Abstract Endometriosis, a chronic gynecological disorder defined as the presence of endometrial glands and stroma outside the endometrial cavity, is characterized by peritoneal inflammation, fibrosis, adhesions and ovarian cysts. Patients suffer from chronic pelvic pain, pain during intercourse, painful periods and infertility. This condition remains poorly understood with limited treatment, and continues to affect the productivity and lifestyle of millions of women around the world causing high levels of psychological and emotional distress. Our study aims to shed light on possibilities for an entirely new therapeutic approach for patients with endometriosis. Our previous studies have shown that exposure to stress and modulation of the hypothalamic- pituitary-adrenal (HPA) axis exacerbates the development and severity of endometriosis. The goal of this proposal is to extend our prior results by investigating the impact of exercise, a therapy that could be easily extrapolated to the patient population. There is already evidence that exercise can act as a stress buffer with beneficial effects in many chronic conditions, most likely via suppression of the immune system and HPA axis regulation. A recent systematic review and meta-analysis suggest that physical activity may reduce the risk of endometriosis. However, until now no specific experimental data exist regarding the impact of exercise as an intervention on the course of endometriosis. This study will test the hypothesis that physical exercise can ?realign/reset? dysregulation of the brain-gut axis caused by stress resulting in reduced endometriosis symptoms in an animal model. Under Specific Aim 1, we will expose our endometriosis animals to exercise before/during and after the induction of endometriosis under non-stress conditions, examining its impact on vesicle and intestinal pathology, cytokines, behavior, hippocampal expression of CRF, and the intestinal microflora. In Specific Aim 2 we will identify how exercise interventions can reduce or prevent the stress-induced exacerbation of endometriosis, examining the impact of timing on the endpoints outlined above. This study will contribute to the goals of the AREA program by strengthening the institutional environment and exposing students at various levels to multidisciplinary research areas, thus offering a unique training opportunity to encourage their continued involvement in biomedical sciences research. Our long-term goal is to implement behavioral and stress-reduction strategies as part of an integrated clinical management plan for endometriosis Outcomes from this study will also further enhance our understanding of the neuro-immune system in women?s health.